What are the main undesirable side effects of TZDs and with what mechanisms have they been explained

Ankle oedema constitutes an undesirable side effect of TZDs manifesting at a rate of 4-5 percent of patients. Fluid retention, which is partly responsible for the increase of body weight that is observed in patients treated with TZDs, can decompensate preexisting cardiac insufficiency, or cause the development of cardiac insufficiency that was not previously diagnosed. In this case, diuretics do not help and discontinuation of the TZD is imperative. If insulin is coadministered, the oedema can be more intense and more frequent (roughly 15 percent). The patients should be informed about the possibility of the increase of body weight and be stricter with their diet. Various mechanisms for the appearance of oedema have been proposed: increase of plasma volume, increased renal sodium reabsorption, activation of the sympathetic reflex, disturbances of intestinal reabsorption of ions and increased production of vascular endothelial growth factor.

Apart from water retention, an increase of the total body fat can also contribute to the increase of body weight, as has been shown in many studies. The increase of body weight is around 2-4 kg (4.4-8.8 lb) in the first 6-12 months of treatment and concerns the increase of peripheral and not splanchnic fat. When combined with sulfonylureas the increase of weight is usually larger and is highest in combination with insulin (56 kg [11.0-13.2 lb]). There have been infrequent cases of weight gain up to 20 kg (44.1 lb) on treatment with TZDs, with no explanation why. When this increase is very large, several authors recommend interruption of TZDs.

Fluid retention can also cause anaemia because of haemodilution. The haematocrit can be decreased by 1-2 percent and the haemoglobin by around 1 g/dl. This reduction presents in the first 12 weeks of treatment and appears to reflect an increase in the volume of blood, since the red blood cells mass remains stable. Some authors report a small reduction of white blood cells and platelets.

Hepatic damage can occasionally present as a side effect of TZDs. In reality, because of the reduction of insulin resistance, these medicines are expected to decrease the intrahepatic fat concentration and the fat infiltration that is observed in obesity and DM. As a matter of fact, recent studies have shown an improvement of clinical and pathologic characteristics of patients with non-alcoholic steatohepatitis after treatment with TZDs, without increase of the transaminase levels. The transaminases should in any case be regularly monitored (before therapy and every two months in the first year, and less frequently thereafter). Troglitazone, the first TZD that was used for treatment, was withdrawn because of significant hepatic complications. The latest experience with the available TZDs is reassuring as regards the probability of hepatocellular damage.

Most writers also stress the increased cost of TZDs compared to other antidiabetic pills.

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